Finally, MMP-9 has been identified as one of the factors partially mediating this process.97 Interestingly, in breast cancer cells, HRG-induced MMP-1 and MMP-9 expression is mediated through HER3-dependent pathway and cells with higher HER2 level is more aggressive than those with the lower HER2 expression.98 A potential signature of brain metastasis marker HER2+/EGFR+/HPSE+/Notch1+ in EpCAM-negative CTCs has been identified as high invasive and capable of generating brain and lung metastases in xenograft model.99 The gene discussed is MMP9; the disease is breast carcinoma.